P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis

Author(s):Show less -

Santiago-Carvalho, Igor ^[1] ; de Almeida-Santos, Gislane ^[1] ; Barbosa Bomfim, Caio Cesar ^[1] ; de Souza, Paula Carolina ^[1] ; Santos e Silva, Juan Carlo ^[2] ; Silva de Melo, Bruno Marcel ^[3] ; Amaral, Eduardo Pinheiro ^[4] ; Pinheiro Cione, Marcos Vinicios ^[1] ; Lasunskaia, Elena ^[5] ; Hirata, Mario Hiroyuki ^[2] ; Farias Alves-Filho, Jose Carlos ^[3] ; Nakaya, Helder Imoto ^[2] ; Alvarez, Jose Maria ^[1] ; D'Imperio Lima, Maria Regina ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed ICB, Dept Imunol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut FCF, Dept Anal Clin & Toxicol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Farmacol, Sao Paulo - Brazil

^[4] NIAID, Immunobiol Sect, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[5] Univ Estadual Norte Fluminense, Lab Biol Reconhecer, Campos Dos Goytacazes - Brazil

• Document type: Journal article
• Source: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY; v. 11, MAY 5 2021.
• Web of Science Citations: 0

Abstract

The risk of developing severe forms of tuberculosis has increased by the acquired immunodeficiency syndrome (AIDS) epidemic, lack of effective drugs to eliminate latent infection and the emergence of drug-resistant mycobacterial strains. Excessive inflammatory response and tissue damage associated with severe tuberculosis contribute to poor outcome of the disease. Our previous studies using mice deficient in the ATP-gated ionotropic P2X7 receptor suggested this molecule as a promising target for host-directed therapy in severe pulmonary tuberculosis. In this study, we assessed the effects of P2X7 pharmacological blockade on disease severity. First, we observed an increase in P2RX7 gene expression in the peripheral blood of tuberculosis patients compared to healthy donors. Lung leukocytes of mice infected with hypervirulent mycobacteria also showed increased expression of the P2X7 receptor. P2X7 blockade in mice with advanced tuberculosis recapitulated in many aspects the disease in P2X7-deficient mice. P2X7-directed therapy reduced body weight loss and the development of inflammatory and necrotic lung lesions, as well as delayed mycobacterial growth. Lower TNF-alpha production by lung cells and a substantial reduction in the lung GR-1(+) myeloid cell population were observed after P2X7 inhibition. The effector CD4(+) T cell population also decreased, but IFN-gamma production by lung cells increased. The presence of a large population with characteristics of myeloid dendritic cells, as well as the increase in IL-6 production by lung cells, also indicate a qualitative improvement in the pulmonary immune response due to P2X7 inhibition. These findings support the use of drugs that target the P2X7 receptor as a therapeutic strategy to improve the outcome of pulmonary tuberculosis. (AU)

• FAPESP's process: 19/24700-8 - Role of P2X7 receptor on parenchymal and intravascular CD4 T cell response in a Severe Experimental Tuberculosis model
• Grantee: Igor Santiago de Carvalho
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/27139-5 - Application of genomic tools for the study of epidemiological databases
• Grantee: Juan Carlo Santos e Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 20/09043-8 - Purinergic signaling in the pathogenesis of Acute Lung Injury and Acute Respiratory Distress Syndrome associated with pulmonary Malaria
• Grantee: Caio César Barbosa Bomfim
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/11030-9 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis
• Grantee: Paula Carolina de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/20432-8 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis
• Grantee: Maria Regina D'Império Lima
• Support Opportunities: Research Projects - Thematic Grants